Escalation with Overdose Control using a Toxicity Score for Personalized Maximum Tolerated Dose in Phase I Clinical Trials 公开

Zhuang, Run (2016)

Permanent URL: https://etd.library.emory.edu/concern/etds/1544bp316?locale=zh
Published

Abstract

The goal of many cancer Phase I clinical trials is to establish the level of dose toxicity tolerance in order to estimate the maximum tolerated dose (MTD) used for future trials. Common methods are divided into rule-based and model-based methods for dose escalation. The most popular method currently used is the 3+3 rule-based design. This method is simple and convenient, but has been shown to predict the true MTD in about 35% of trials. Model-based designs establish a dose response relationship that is equal to a pre-specified probability of dose limiting toxicity (DLT). Escalation with overdose control (EWOC) is a Bayesian adaptive design for selecting dose levels in cancer Phase I clinical trials while controlling the posterior probability of exceeding the MTD. We extend EWOC to incorporate a novel toxicity score with the addition of covariates for personalized medicine (EWOC-NETS with covariates). Under our extensions, we found significant differences in the estimated MTD between EWOC, EWOC-NETS, and EWOC-NETS with covariates for 4 simulated scenarios. Our developed method is also safer with respect to toxicity and overdosing.

Table of Contents

List of Tables i

List of Figures ii

1 Introduction 1

1.1 Rule-Based Methods in Phase I Trials 2

1.2 Model-Based Methods in Phase I Trials 3

1.3 Escalation with Overdose Control (EWOC) 4

1.4 Extensions and Goals 6

2 Methods 7

2.1 EWOC 8

2.2 NETS 10

2.3 EWOC-NETS 12

2.4 EWOC-NETS with a Discrete Covariate 14

2.5 EWOC-NETS with a Continuous Covariate 16

2.6 Simulation Settings and Methods 17

3 Results 21

3.1 Discrete Covariate 21

3.2 Continuous Covariate 24

4 Discussion 28

5 Bibliography 30

6 Appendix 32

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